Thursday, April 25, 2024
4/25/2024
Project summary Host pattern recognition receptors, such as retinoic acid-induced gene I (RIG-I), sense viral RNA and elicit interferon-mediated innate immunity to restrict viral infection. It is well-established that RIG-I induces type I interferon (IFN) expression via the mitochondrial antiviral signaling protein (MAVS) and TANK-binding kinase 1 (TBK1). Type I IFN acts a danger signal and further activates the JAK-STAT signaling pathway to induce interferon-stimulated genes (ISGs), thereby limiting viral infection. A recent study reported another RIG-I signaling branch, in which MAVS directly induces STAT1 phosphorylation and ISG expression through the tyrosine kinase SYK. The RIG-I-STAT1 signaling has been shown to be critical for host defense at the early stage of viral infection. However, the critical intermediate signal molecule(s) linking MAVS and SYK is missing in this signal cascade because MAVS does not have the immunoreceptor tyrosine-based activation motif (ITAM) responsible for SYK binding and activation. Thus, there is a knowledge gap in the RIG-I-STAT1 signaling pathway. The objective in this application is to determine the role of the ovarian cancer immunoreactive antigen domain containing 1 (OCIAD1) in the RIG-I-STAT1 signaling pathway and host defense to viral infection. Although the RIG-I-STAT1 signaling pathway is established recently, there is a missing link between MAVS and SYK. Bioinformatic analysis showed that OCIAD1 had an ITAM-like motif that can recruit and activate SYK. Our preliminary data and previous studies showed that OCIAD1 interacted with MAVS. Furthermore, deficiency of OCIAD1 impaired RIG-I-mediated STAT1 phosphorylation. In addition, we and others reported that the NS2 protein of influenza A virus interacted with OCIAD1. Overexpression of NS2 blocked STAT1 phosphorylation. Thus, based on the existing literature and our preliminary data, we hypothesize that OCIAD1 recruits SYK to the MAVS signalosome and activates STAT1 phosphorylation in the RIG-I-STAT1 signaling pathway. Furthermore, influenza NS2 suppresses the RIG-I-STAT1 signaling pathway by antagonizing OCIAD1. Aim 1 will determine the role of OCIAD1 in IAV infection in vivo and in human primary cells. Aim 2 will dissect the molecular mechanisms of how OCIAD1 regulates the RIG-I-STAT1 signaling and how NS2 antagonizes this pathway. Our study will bridge the gaps in the RIG-I-STAT1 signaling cascades and determine a potential role of NS2 in subversion of host innate immune response, which will provide insights on a new viral strategy for evading host defense surveillance. The findings in our study will not only help develop effective antiviral therapeutics but will also deepen our understanding of host innate immune responses to viruses.
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